While vaccination is one of the most effective public health interventions, stringent attention must be paid to its safety. Vaccines in national vaccination programs are generally safe, but on rare occasions some individuals experience serious adverse events. In addition to the suffering of the individual, the occurrence of adverse events may also compromise public confidence in vaccination. If researchers and clinicians can learn through which mechanisms adverse events occur, they will be able to improve the design of vaccines to make them safer, develop tests to predict risk of adverse events and, subsequently, take appropriate preventive measures in certain high risk individuals. An increased risk of febrile seizures has been observed in children in the immediate period following administration of the measles, mumps and rubella (MMR) vaccine. It has been estimated that 3 to 16 additional cases of febrile seizures per 10,000 children can be attributed to MMR vaccination. Preliminary studies have suggested that adverse events of vaccination may have genetic determinants. The aim of this project is to investigate whether any genetic variants (polymorphisms) are associated with increased risk of febrile seizures following MMR vaccination. This project, the first of its kind, will apply modern genetics technology and analyze more than 1,000,000 genetic variants in 1000 children who have suffered febrile seizures following MMR vaccination, 1000 children who have suffered febrile seizures unrelated to MMR vaccination and 1000 healthy controls. A replication study, always necessary to verify results in large genetics studies, will involve an additional 2000 children. The project will take advantage of the exceptional research resources available in Denmark and will combine health information from nationwide registers with genetic information based on samples obtained from a national biobank. This study will not only provide new insights into the safety of the MMR vaccine, but will demonstrate the feasibility and value of studying the genetics of vaccine safety in general. PUBLIC HEALTH RELEVANCE: This project aims to investigate the genetic determinants of an adverse event - febrile seizures - following measles, mumps and rubella vaccination. National vaccination programs fighting infectious diseases are of vital importance to public health and their safety must be as close to perfection as possible. Learning the mechanisms through which adverse events occur has important implications for the future design of vaccines and for the practice of vaccination.